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Rational Drug Design Using the 3D Shape of Proteins to Design Drugs that Inhibit Protein Function Before you start this activity, make sure you have the program Cn3D installed on your computer. Download Cn3d from this site Examples of Protein Function Hormones

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rational drug design

Rational Drug Design

Using the 3D Shape of Proteins to Design Drugs that Inhibit Protein Function

Before you start this activity, make sure you have the program Cn3D installed on your computer.

Download Cn3d from this site


Examples of Protein Function


Insulin binds to receptors on cell membranes signalling cells to take up glucose from the blood

Protein ChannelsRegulate movement of substances across the plasma membrane. E.g. The CFTR protein pumps ions across membranes


Haemoglobin (far right) in red blood cells transports oxygen to cells around the body

Source: http://www.biology.arizona.edu/biochemistry/tutorials/chemistry/page2.html




catalase enzyme power
Catalase - enzyme power!

Hydrogen peroxide, a natural product of metabolism in your cells, is highly toxic in high concentrations and must be removed quickly!




Add ferric ions (Fe 3+)

Rate increases 30 000-fold




Hydrogen peroxide

Add Catalase

Rate increases 100 000 000-fold

Location of active site where

Hydrogen peroxide binds

Source: http://accad.osu.edu/~ibutterf/ibp/molecule/



how enzymes do it
How enzymes do it!
  • Enzyme proteins have specific sites where all the action happens. We call this the active site. Molecules that need to be ripped apart or put together enter the active site.
  • Each protein has a specific shape so it will only perform a specific job.

Ripping things apart

Joining things together



many toxins are proteins
Many toxins are proteins

Ricin from the seeds of the castor oil plant destroys ribosomes

Funnel web spider toxin: blocks movement of calcium ions.

Source: http://www.wiley.com/legacy/college/boyer/0470003790/cutting_edge/molecular_recognition/molecular_recognition.htm



protein molecules are polymers
Protein molecules are polymers
  • Proteins are very large polymer molecules. Polymers are made by linking smaller molecules, monomers, together to make a long chain.
  • In the case of proteins, the monomers are amino acids. There are 20 different amino acids.








why is protein structure important
Why is protein structure important?
  • Each protein molecule has a characteristic 3D shape that results from coiling and folding of the polymer chain.
  • The function of a protein depends upon the shape of the molecule.
protein chains
Protein chains

Each protein has a specific sequence of amino acids that are linked together, forming a polypeptide


the protein chain folds
The protein chain folds

Interactions between amino acids in the chain form:

  • alpha helices
  • beta sheets
  • Random coils

Together usually form the binding and active sites of proteins

Source: http://www.rothamsted.bbsrc.ac.uk/notebook/courses/guide/prot.htm#I

and folds again
And folds again!
  • After folding, amino acids that were distant can become close
  • Now the protein chain has a 3D shape that is required for it to function correctly

Source: io.uwinnipeg.ca/~simmons/ cm1503/proteins.htm

the final protein
The final protein…

The final protein may be made up of more than one polypeptide chain.

The polypeptide chains may be the same type or different types.

Source: http://fig.cox.miami.edu/~cmallery/150/chemistry/hemoglobin.jpg

designing a drug to block amylase action
Designing a Drug to Block Amylase Action

Amylase is a protein that cuts small maltose sugar molecules off starch molecules.

Another enzyme, maltase, is responsible for breaking down the maltose molecules into two simple sugars known as glucose.

Glucose is absorbed into the blood and transported to cells around the body to provide them with energy.








your turn designing a diet pill
Your turn…Designing a diet pill

Click on the button on the right to start exploring amylase with its active site blocked by a drug.

Amylase in Cn3D

influenza pandemics
Influenza Pandemics

The Spanish Flu in 1918, killed approximately 50 million people. It was caused by the H1N1 strain of influenza A.

The Asian Flu in 1957 was the H2N2 influenza A strain. Worldwide it is estimated that at least one million people died from this virus.

The Hong Kong Flu in 1968 evolved into H3N2. 750,000 people died of the virus worldwide

influenza epidemics
Influenza epidemics
  • Economic Effects:
  • Days away from work
  • Providing medical advise and treatment
  • Mortalities

Figure 1. Weekly number of influenza and pneumonia deaths per 10 000 000 population in the United States, France, and Australia (black line).


Designing a Flu Drug Step 1: looking for protein targets

Influenza viruses are named according to the proteins sticking out of their virus coat.


There are two types of protein = Nand H.

N and H have special shapes to perform specific jobs for the virus.



N cuts the links between the viruses and the cell surface so virus particles are free to go and infect more cells.

H attaches to cell surface proteins so virus can enter cell


Proteins on cell surface

Virus genes are released into the cell.

The lung cell is ‘tricked’ into using these genes to make new virus particles.

Human Lung Cell

Your turn…Explore the research of an Australian team of scientists headed by Prof Peter Coleman. They designed the flu drug, Relenza.

Source: http://www.vnn.vn/dataimages/original/images126851_relenza.jpg


blocking the active site
Blocking the active site


in Cn3D


This link will open a Cn3D file of Neuraminidase with the drug relenza blocking its active site

venoms to drugs
Venoms to drugs

Link to watch movie

A team of scientists from Melbourne University have patented a toxic chemical from the venom of an Australian Cone Shell.

The chemical, called ACV1, is an analgesic that will help relieve chronic pain. It is more powerful than morphine and is not addictive.

This analgesic will be used to treat pain resulting from nerve injury, post-surgical pain, “phantom limb” pain in amputees, leg ulcers in diabetics or the pain of terminal AIDS or cancer.

ACV1 treats pain by blocking the transmission of pain along our peripheral nervous system

This drug could generate an annual profit of greater than1 billion dollars to the company that develops it!

Source: http://www.unimelb.edu.au/ExtRels/Media/02media/02july08.html

some facts
Some facts…
  • Calcium, sodium and potassium ions control essential functions inside cells: calcium, for example, helps regulate the contraction of muscle cells.
  • Ion channels control the entry and exit of ions into and out of cells.
  • Some conotoxins act as analgesics, interacting with ion channel receptors in nerves so the ion channel cannot open. Blocking ion channels stops ions from entering a neighbouring nerve fibre. No electrical impulse is set off so the ‘pain’ message is switched off! Phew!
the nerve impulse

Sodium ion

Calcium ion


The nerve impulse

3.Influx of Calcium causes acetylcholine to be released into synaptic junction.

Synaptic Junction







2. Sodium ions accumulate causing Calcium ion channels to open.





4. Acetylcholine binds with receptor proteins changing the shape of the ion channel.

5. This opens the sodium ion channel to let in sodium.

6. Sodium ions set off an electrical impulse along the next nerve cell.

7. The pain message is working.

1. Electrical impulse generated along axon – sodium ions (red) rush in and Potassium ions (green) rush out

To block pain we can try to target the ion channels.

acetylcholine at work
Acetylcholine at work

Below is an image of a section of a nerve cell cut open to reveal one of the Sodium Ion channels that studs its surface. Let’s slice through an ion channel to show its inner workings..

2 Acetylcholine molecules bind to Receptor binding protein on an ion channel.

The shape of the ion channel protein changes so the Na+ gate opens.

Ions move into the neuron setting off an impulse.

The message is passed on!

Outside Cell

Inside Cell

na ion channel
Na+ ion channel

You will explore this part of the ion channel.

This is the section that binds acetylcholine &/or drug molecules causing the ion channel to change its shape.

Outside neuronal cell

Cell membrane (Phospholipid bylayer)

Inside neuronal cell

Some conotoxins block acetylcholine (nACh) receptors that stud the surface of neurons. Let’s eplore this ion channel in Cn3D

your turn explore the action of a natural pain killer
Your turn…Explore the action of a natural Pain Killer

Follow in the footsteps of Associate Professor Bruce Livett and his team to explore how conotoxins can block nerve impulses, stopping pain.

Ion Channel with


Ion Channel

with Drug

alpha conotoxin A

Alpha conotoxin B

Source: http://www.theage.com.au/news/creative--media/painkiller-comes-out-of-its-shell/2005/07/24/1122143728598.html